Beta-lactamase inhibitors and uses thereof
β-Lactamase inhibiting compounds, therapeutic methods of using the β-lactamase inhibiting compounds, particularly in combination with β-lactam antibiotics and pharmaceutical compositions thereof are disclosed. The β-lactamase inhibiting compounds are suitable for oral administration.
1. A compound of Formula (1):
or a pharmaceutically acceptable salt thereof, wherein,
each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;
R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl; and
R 3 is selected from C 1-6 alkyl, —O—C(O)—R 4 , —S—C(O)—R 4 , —NH—C(O)—R 4 , —O—C(O)—O—R 4 , —S—C(O)—O—R 4 , —NH—C(O)—O—R 4 , —C(O)—O—R 4 , —C(O)—S—R 4 , —C(O)—NH—R 4 , —O—C(O)—S—R 4 , —O—C(O)—NH—R 4 , —S—S—R 4 , —S—R 4 , —NH—R 4 , —CH(—NH 2 )(—R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 5-6 aryl, substituted C 5-6 heteroaryl, and —CH═C(R 4 ) 2 , wherein,
R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl.
2. The compound of claim 1 , wherein each R 1 is independently selected from C 1-6 alkyl.
3. The compound of claim 1 , wherein R 2 is selected from a single bond, C 1-6 alkanediyl, C 5-6 cycloalkanediyl, and C 6 arenediyl.
4. The compound of claim 1 , wherein,
R 3 is selected from C 1-6 alkyl, —O—C(O)—R 4 , —S—C(O)—R 4 , —NH—C(O)—R 4 , —O—C(O)—O—R 4 , —S—C(O)—O—R 4 , —NH—C(O)—O—R 4 , —C(O)—O—R 4 , —C(O)—S—R 4 , —C(O)—NH—R 4 , —O—C(O)—S—R 4 , —O—C(O)—NH—R 4 , —S—S—R 4 , —S—R 4 , —NH—R 4 , —CH(—NH 2 )(—R 4 ), C 5-6 cycloalkyl, and —CH═C(R 4 ) 2 ; and
R 4 is selected from hydrogen, C 1-8 alkyl, C 5-8 cycloalkyl, C 5-10 cycloalkylalkyl, C 6-8 aryl, and C 7-10 arylalkyl.
5. The compound of claim 1 , wherein,
R 2 is selected from a single bond, C 1-6 alkanediyl, C 5-6 cycloalkanediyl, C 6 arenediyl;
R 3 is selected from C 1-6 alkyl, —O—C(O)—R 4 , —S—C(O)—R 4 , —NH—C(O)—R 4 , —O—C(O)—O—R 4 , —S—C(O)—O—R 4 , —NH—C(O)—O—R 4 , —C(O)—O—R 4 , —C(O)—S—R 4 , —C(O)—NH—R 4 , —O—C(O)—O—R 4 , —O—C(O)—S—R 4 , —O—C(O)—NH—R 4 , —S—S—R 4 , —S—R 4 , —NH—R 4 , —CH(—NH 2 )(—R 4 ), C 5-6 cycloalkyl, and —CH═C(R 4 ) 2 ; and
R 4 is selected from hydrogen, C 1-8 alkyl, C 5-8 cycloalkyl, C 5-10 cycloalkylalkyl, C 6-8 aryl, and C 7-10 arylalkyl.
6. The compound of claim 1 , wherein,
each R 1 is independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
R 2 is selected from single bond, methane-diyl, and ethane-diyl; and
R 3 is selected from —C(O)—O—R 4 and —S—C(O)—R 4 , wherein R 4 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-10 arylalkyl, C 5-8 heterocycloalkyl, and substituted C 5-10 heterocycloalkylalkyl.
7. The compound of claim 1 , wherein,
each R 1 is independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
R 2 is a single bond; and
R 3 is —(O)—O—R 4 , wherein R 4 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-10 arylalkyl, C 5-8 heterocycloalkyl, and substituted C 5-10 heterocycloalkylalkyl.
8. The compound of claim 1 , wherein,
each R 1 is independently selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
R 2 is —(CH 2 ) 2 —; and
R 3 is —C(O)—O—R 4 wherein R 4 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-10 arylalkyl, C 5-8 heterocycloalkyl, and substituted C 5-10 heterocycloalkylalkyl.
9. The compound of claim 1 , wherein,
each R 1 is selected from C 1-3 alkyl, or each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring;
R 2 is —CH 2 —; and
R 3 is —S—C(O)—R 4 , wherein R 4 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-10 arylalkyl, C 5-8 heterocycloalkyl, and substituted C 5-10 heterocycloalkylalkyl.
10. The compound of claim 1 , wherein,
each R 1 together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a C 3-6 cycloalkyl ring, or a C 3-6 heterocycloalkyl ring;
R 2 is a single bond; and
R 3 is C 1-3 alkyl.
11. The compound of claim 1 , wherein,
each R 1 is independently selected from C 1-3 alkyl;
R 2 is selected from a single bond and methanediyl; and
R 3 is selected from —O—C(O)—R 4 and —C(O)—O—R 4 , wherein R 4 is selected from C 1-8 alkyl and substituted phenyl.
12. The compound of claim 1 , wherein,
each R 1 is independently selected from C 1-3 alkyl;
R 2 is a single bond; and
R 3 is —CH═C(R 4 ) 2 , wherein each R 4 is —C(O)—O—R 8 and
each R 8 is C 1-4 alkyl.
13. The compound of claim 1 , wherein,
each R 1 is independently selected from C 1-3 alkyl;
R 2 is selected from a single bond and methanediyl; and
R 3 is substituted phenyl, wherein the one or more substituents is independently selected from —CH 2 —O—C(O)—R 4 and —O—C(O)—R 4 , wherein R 4 is selected from C 1-8 alkyl and phenyl.
14. The compound of claim 1 , wherein,
each R 1 is independently selected from C 1-3 alkyl;
R 2 is selected from —C(R 8 ) 2 — and —CH 2 —C(R 8 ) 2 —,wherein each R 8 is independently selected from C 1-3 alkyl; and
R 3 is selected from —C(O)—O—R 4 and —OC—(O)—R 4 , wherein R 4 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, and 4(yl-methyl)-5-methyl-1,3-dioxol-2-one.
15. The compound of claim 1 , wherein, each R 1 together with the carbon atom to which they are bonded form a substituted C 5-6 heterocyclic ring;
R 2 is a single bond; and
R 3 is C 1-3 alkyl.
16. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.
17. The pharmaceutical composition of claim 16 , further comprising an antibiotic.
18. The pharmaceutical composition of claim 17 , wherein the antibiotic comprises a β-lactam antibiotic.
19. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is an oral dosage formulation.
20. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is an oral dosage form.
21. A method of treating a bacterial infection in a patient comprising administering to a patient having the bacterial infection a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a β-lactam antibiotic, wherein bacteria causing the bacterial infection produces a β-lactamase.
22. The method of claim 21 , wherein administering comprises orally administering.
23. A method of treating a bacterial infection in a patient comprising administering to a patient having the bacterial infection a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a β-lactam antibiotic, wherein the bacterial infection is capable of being treated with a therapeutically effective amount of the β-lactam antibiotic when co-administered with a therapeutically effective amount of avibactam.
24. The method of claim 23 , wherein administering comprises orally administering.
25. A method of inhibiting a β-lactamase enzyme in a patient, comprising administering to a patient an effective amount of the compound of claim 1 to the patient.
26. The method of claim 25 , wherein administering comprises orally administering.